The term avermectin (previously referrred to as C-076) is used to describe a series of compounds isolated from the fermentation broth of an avermectin producing strain of Streptomyces avermitilis and derivatives thereof. The morphological characteristics of the culture are completely described in U.S. Pat. No. 4,310,519. The avermectin compounds are a series of macrolides, each of which is substituted thereon at the 13-position with a 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group. The avermectin compounds and the instant derivatives thereof have a very high degree of anthelmintic and anti-parasitic activity.
The avermectin series of compounds isolated from the fermentation broth having the following structure: ##STR1## wherein R is the 4'-(.alpha.-1-oleandrosyl)-.alpha.1-oleandrose group of the structure: ##STR2## and wherein the broken line indicates a single or a double bond; R.sub.1 is hydroxy and is present only when said broken line indicates a single bond;
R.sub.2 is iso-propyl or sec-butyl; and PA1 R.sub.3 is methoxy or hydroxy. PA1 R.sub.2 is methyl, ethyl, isopropyl or sec-butyl; PA1 R.sub.3 is OH, OCH.sub.3, loweralkanoyloxy or OR; PA1 R.sub.4 is H, OH, OR, loweralkanoyloxy, .alpha.-L-oleandrosyloxy, .alpha.-L-oleandrosyl-a-L-oleandrosyloxy, 4'-loweralkanoyl-.alpha.-L-oleandrosyloxy, 4"-loweralkanoyl-4'-.alpha.-L-oleandrosyl-.alpha.-L-oleandrosyloxy, ##STR4## R.sub.5 is H or OR; and R is the phosphate ester groups P(O)(OH)(OMe), P(O)(OMe).sub.2, P(O)(OCH.sub.2 CCl.sub.3).sub.2, P(O)(OH).sub.2, P(O)(OH)(OM), P(O)(OM).sub.2, P(O)(OH)O.sup.- (H.sub.3 N.sup.+ -alk), P(O)(O.sup.-).sub.2 (H.sub.3 N.sup.+ alk).sub.2,
There are eight different major avermectin natural product compounds and they are given the designations A1a, A1b, A2a, A2b, B1b, and B2a based upon the structure of the individual compounds.
In the foregoing structural formula, the individual avermectin compounds are as set forth below. (The R group is 4'(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose):
______________________________________ R.sub.1 R.sub.2 R.sub.3 ______________________________________ A1a Double Bond sec-butyl --OCH.sub.3 A1b Double Bond iso-propyl --OCH.sub.3 A2a --OH sec-butyl --OCH.sub.3 A2B --OH iso-propyl --OCH.sub.3 B1a Double Bond sec-butyl --OH B1b Double Bond iso-propyl --OH B2a --OH sec-butyl --OH B2b --OH iso-propyl --OH ______________________________________
The avermectin compounds are generally isolated as mixtures of a and b components. Such compounds differ only in the nature of the R.sub.2 substituent and the minor structural differences have been found to have very little effect on the isolation procedures, chemical reactivity and biological activity of such compounds.
Milbemycin compounds are similar to the above avermectin compounds in that the 16-membered macrocyclic ring is present. However, such compounds have no substitution at the 13-position and have a methyl or ethyl group at the 25-position (the position the R.sub.2 group is found in the above structure). To the extent that such milbemycin compounds have hydroxy groups or can be converted to compounds with hydroxy groups which can then be substituted with the instant phosphate groups, they are to be construed as being within the ambit of this invention. Such milbemycin compounds and the fermentation conditions used to prepare them are described in U.S. Pat. No. 3,950,360. In addition, 13-deoxyavermectin aglycones are prepared synthetically from the avermectin natural products and are disclosed in U.S. Pat. Nos. 4,171,134 and 4,173,571. Such compounds are very similar to the milbemycins differing from some of the milbemycins in having an isopropyl or sec butyl rather than a methyl or ethyl group at the 25-position.